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1、RegulationofmicroRNAprocessinganditsimplicationsfordevelopmentandcancerJ.MichaelThomsonTheHammondLab1Thomson,J.M.2MicroRNAexpressionprofilesThomsonandHammond,unpublisheddata3EvolutionaryConservedmiRNACluster4miR17-92isConservedinVertebrates5miR-17-92isAmplifiedinLymphomaOta,et.al.,C
2、ancerRes.200464:3087-956Themir17-92clusterresidesinaregionwithknownamplificationsincasesofDLBCL,follicularandmantlecelllymphoma,andseverallungandhead/neckcarcinomasLymphomacelllineswithknownamplificationforC13orf25exhibithighlevelexpressionformiR17-92comparedtocelllineslackingamplifi
3、cation.Allcelllinesexhibitreducedexpressionoflet7familymemberscomparedtocordbloodB-cellsmiR-17-92isAmplifiedinLymphomaHe,etalNature435(7043):828-3320057OverexpressionofmiR-17-19binaMouseModelofHumanLymphoma8ExpressionofmiR17-19bResultsinB-cellLymphomaHe,etalNature435(7043):828-332005
4、9miR-17-92isregulatedbyE2Ftranscriptionfactors10MicroRNAexpressionprofilesThomsonandHammond,unpublisheddata11OncomiR-1andLet-7familyareinverselyexpressedindevelopmentandcancerTumorigenesisDevelopmentThomsonandHammond,unpublisheddataThemicroRNAhypothesisofcancerTumorsdown-regulatemany
5、microRNAstopromotea“stemcell”likestateSelectedmicroRNAs(oncomiRs)areexpressedatahighleveltopromoteproliferationandsuppressapoptosisWhatisthemechanismforwidespreadalterationsingeneExpression?Transcription,processing,turnover?14TranscriptionalreactivationwithmethylaseandHDACInhibitorsr
6、esultsintheactivationof17/313microRNAsAsimilarstudyof15microRNAsoftendown-regulatedinCancerfrom91cancercelllinesrevealedlesionsthatoftendisruptedthesecondarystructureofthepri-miRNA,buthavelittleornoeffectonexpressionGeneticdeletionscanexplainsomecasesofmicroRNAloss,buttheseareoftenli
7、mitedtospecificindividualcases.Anotherpossibilitycouldberegulatedprocessing,asmanymicroRNAsresideintheintronsofcommonhousekeepingmRNAs.Saito,Y.,etalCancerCell2006;Diederichs&HaberCancerRes.2006;Calin,GA.,etalPNAS2002,200415ExonicNon-codingMicroRNAsaretranscribedbyRNAPolymeraseIIIntro
8、nicNon-codin